Despite the wide use and acceptance of penicillins and cephalosporins, beta-lactam antibiotics, in combating bacterial infections, there are certain members within the group that are not active against resistant microorganisms because of the organism's ability to produce a beta-lactamase enzyme which reacts with beta-lactam antibiotic to produce products devoid of antibacterial activity. However, certain substances have the ability to inhibit beta-lactamases, and when used in combination with a penicillin or cephalosporin can increase or enhance the antibacterial effectiveness of the antibiotic against certain beta-lactamase producing microorganisms.
West German Offenlegungsschrift No. 2,824,535 published Dec. 14, 1978 teaches that penicillanic acid sulfone is such an effective beta-lactamase inhibitor. In addition, it is taught in said application that certain esters of penicillanic acid sulfone are readily hydrolyzable in vivo giving high blood levels of this beta-lactamase inhibitor. Further, U.K. patent application No. 2,044,255 and Belgian Pat. No. 883,299 also teaches that halomethyl esters of penicillanic acid sulfone can be useful intermediates in the synthesis of readily hydrolyzable esters which degrade in vivo into penicillanic acid sulfone and a beta-lactam antibiotic.
In this latter reference the preferred method for preparing the appropriate halomethyl ester of penicillanic acid sulfone comprises the reaction of a salt of said acid with a dihalomethane. While operable, this method leads to unwanted by-products resulting from the reaction of two moles of the acid with one mole of dihalomethane or, alternately considered, a further reaction of halomethyl ester with a second mole of penicillanic acid sulfone salt.
The present invention relates to a process for the synthesis of halomethyl esters of penicillanic acid sulfone which avoids the above mentioned by-product formation. In addition, the invention further relates to useful intermediates for the instantly claimed process.
Chloromethyl esters of simple acids have been prepared through the reaction of the corresponding acid chloride with formaldehyde in the presence of zinc chloride (J. Am. Chem. Soc., 43, 660 (1921), as well as by the reaction of a free acid with formaldehyde and hydrochloric acid in the presence of zinc chloride (Chem. Abst. 53, 4119fg (1959).
N-Chloromethylphthalimide can be formed by the treatment of N-sulfinylmethylphthalimides with sulfuryl chloride, chlorine or thionyl chloride (Chem. Pharm. Bull., 27, 1199 (1979).